Cytochrome P-450-derived eicosanoids participate in the renal functional effects of ET-1 in the anesthetized rat.
We evaluated the contribution of cytochrome P-450 (CYP450)-dependent arachidonic acid (AA) metabolites and prostanoids to the renal hemodynamic and tubular effects of endothelin-1 (ET-1) in anesthetized rats. Either ET-1 (0.3, 1.0, and 3 pmol.kg-1.min-1) or vehicle was infused intravenously during two to three 30-min clearance experimental periods. Only high-dose ET-1 increased mean arterial pressure: control, 75 +/- 3 mmHg vs. experimental, 84 +/- 4 mmHg. A dose-dependent diuretic-natriuretic response to ET-1 occurred despite progressive declines in glomerular filtration rate (GFR) and renal blood flow. In the face of a 36% reduction in GFR in response to the highest dose of ET-1, urinary sodium excretion (UNaV) increased threefold from 0.57 +/- 0.11 to 1.6 +/- 0.10 mumol.100 g-1.min-1. Indomethacin (5 mg/kg) decreased basal GFR from 1.2 +/- 0.3 ml.100 g-1.min-1 to 0.8 +/- 0.1 ml.100 g-1.min-1 and potentiated the GFR lowering action of ET-1 associated with reductions in UNaV and urine volume. Cobalt chloride (CoCl2) and dibromododec-11-enoic acid (DBDD), which diminish CYP450-dependent AA metabolism through different mechanisms, were used to identify CYP450 products mediating the renal functional actions of ET-1. DBDD (12.5 micrograms/min) reduced urinary excretion of 20-hydroxyeicosatetraenoic acid from 3.4 +/- 0.9 (control) to 1.1 +/- 0.6 ng/h and abolished the negative effects of ET-1 on GFR while decreasing the diuretic-natriuretic action of ET-1. Similar effects were produced by CoCl2. Clotrimazole, an inhibitor of epoxygenase activity, was without effect on ET-1-induced renal functional changes. Thus the capacity of ET-1 to enhance prostaglandin production was primarily expressed in terms of positive effects on renal hemodynamics. In contrast, CYP450 products promoted sodium excretion despite negative effects on renal hemodynamics.
Oyekan
A O
AO
Department of Pharmacology, New York Medical College, Valhalla 10595, USA.
McGiff
J C
JC
D000768:Anesthesia, General; D000818:Animals; D003022:Clotrimazole / Q000494:pharmacology; D003035:Cobalt / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015777:Eicosanoids / Q000502:physiology*; D019332:Endothelin-1 / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D015777:Eicosanoids; D019332:Endothelin-1; D005229:Fatty Acids, Monounsaturated; D003035:Cobalt; D003577:Cytochrome P-450 Enzyme System; C018021:cobaltous chloride; D003022:Clotrimazole; D007213:Indomethacin